17-DMAG (Alvespimycin) HCl is an effective inhibitor of Hsp90, with an IC50 value of 62nM [1]. 17-DMAG (Alvespimycin) HCl binds to the ATP binding motif of Hsp90 and inhibits its protein folding protection activity, resulting in the misfolding and degradation of the target proteins of Hsp90 (such as EGFR, AKT, mutant p53 and IKK) [2]. 17-DMAG (Alvespimycin) HCl has anti-tumor effects and can be used in cancer research such as lung cancer, liver cancer, and colon cancer [3-4].
In vitro, 17-DMAG (Alvespimycin) HCl (50-500nM; 24 or 48h) treatment significantly and dose- and time-dependently led to depletion of the target protein IKK in chronic lymphocytic leukemia (CLL) cells and cysteine aspartate-dependent apoptosis, reducing the binding of NF-κB p50/p65 DNA and the transcription of NF-κB target genes [5]. 17-DMAG (Alvespimycin) HCl (0-1000nM; 24h) treatment inhibits the proliferation of osteosarcoma cells in a dose-dependent manner and inhibits the activation of MET protein and the cell cycle progression [6].
In vivo, 17-DMAG (Alvespimycin) HCl (10mg/kg/day; 5 times per week for 16 days; i.p.) treatment significantly reduces the number of white blood cells in the blood of TCL1-SCID transgenic mouse models and prolongs survival [5]. The treatment with 17-DMAG (Alvespimycin) HCl (5mg/kg/day; 3 times per week; i.p.) reduced the incidence and severity of abdominal aortic aneurysms induced by ANG II in mice, weakened the remodeling of the aortic wall, the inflammatory response and the formation of new blood vessels, and decreased the expression of MMP-2 and MMP-9, the level of MDA and the secretion of MCP-1 [7].
References:
[1] Ge J, Normant E, Porter JR, et al. Design, synthesis, and biological evaluation of hydroquinone derivatives of 17-amino-17-demethoxygeldanamycin as potent, water-soluble inhibitors of Hsp90. J Med Chem. 2006;49(15):4606-4615.
[2] Sun X, Bristol JA, Iwahori S, Hagemeier SR, Meng Q, Barlow EA, Fingeroth JD, Tarakanova VL, Kalejta RF, Kenney SC. Hsp90 inhibitor 17-DMAG decreases expression of conserved herpesvirus protein kinases and reduces virus production in Epstein-Barr virus-infected cells. J Virol. 2013 Sep;87(18):10126-38.
[3] Chang Y J, Huang C Y, Hung C S, et al. Glucose-regulated protein 78 mediates the therapeutic efficacy of 17-DMAG in colon cancer cells[J]. Tumor Biology, 2015, 36(6): 4367-4376.
[4] Mellatyar H, Talaei S, Pilehvar-Soltanahmadi Y, et al. Targeted cancer therapy through 17-DMAG as an Hsp90 inhibitor: Overview and current state of the art[J]. Biomedicine & Pharmacotherapy, 2018, 102: 608-617.
[5] Hertlein E, Wagner AJ, Jones J, et al. 17-DMAG targets the nuclear factor-kappaB family of proteins to induce apoptosis in chronic lymphocytic leukemia: clinical implications of HSP90 inhibition. Blood. 2010;116(1):45-53.
[6] Kawano M, Tanaka K, Itonaga I, Iwasaki T, Kubota Y, Tsumura H. The anti-oncogenic effect of 17-DMAG via the inactivation of HSP90 and MET pathway in osteosarcoma cells. Oncol Res. 2023 Jul 21;31(5):631-643.
[7] Qi J, Yang P, Yi B, et al. Heat shock protein 90 inhibition by 17-DMAG attenuates abdominal aortic aneurysm formation in mice[J]. American Journal of Physiology-Heart and Circulatory Physiology, 2015, 308(8): H841-H852.
17-DMAG (Alvespimycin) HCl是一种有效的Hsp90的抑制剂，其IC50值为62nM [1]。17-DMAG (Alvespimycin) HCl与Hsp90的ATP结合基序结合并抑制其蛋白质折叠保护活性，导致Hsp90的靶蛋白（如EGFR、AKT、突变p53和IKK）发生错误折叠和降解 [2]。17-DMAG (Alvespimycin) HCl具有抗肿瘤作用，可用于肺癌、肝癌和结肠癌等癌症研究 [3-4]。
在体外，17-DMAG (Alvespimycin) HCl（50-500nM; 24 or 48h）处理以剂量和时间依赖性方式显著导致慢性淋巴细胞白血病（CLL）细胞中Hsp90的靶蛋白IKK耗尽和半胱氨酸天冬氨酸依赖性凋亡，减少了NF-κB p50/p65 DNA的结合和NF-κB靶基因转录 [5]。17-DMAG (Alvespimycin) HCl（0-1000nM; 24h）处理以剂量依赖性方式抑制骨肉瘤细胞的增殖，并抑制MET蛋白的激活和细胞周期进程 [6]。
在体内，17-DMAG (Alvespimycin) HCl（10mg/kg/day; 5 times per week for 16 days; i.p.）治疗显著降低了TCL1-SCID移植小鼠模型血液中的白细胞数量，并延长了生存期 [5]。17-DMAG (Alvespimycin) HCl（5mg/kg/day; 3 times per week; i.p.）治疗降低了ANG II诱导的小鼠腹主动脉瘤的发生率和严重程度，减弱了主动脉壁的重塑、炎症反应和新生血管形成，并减少MMP-2和MMP-9的表达、MDA水平和MCP-1分泌 [7]。